Treatment of chronic Respiratory failure in COPD patients with non-invasive ventilation: starting at home and selecting the right patient

COPD is a chronic disease with high mortality and morbidity worldwide. Patients
with end-stage COPD frequently develop CHRF associated with end-of-life. In
that stage of disease, treatment options are limited.
Long-term nocturnal NIV has been applied in patients with chronic alveolar
hypoventilation for decades. While there is no doubt that applying chronic
nocturnal NIV improves outcomes in patients with restrictive and neuromuscular
diseases, the evidence in COPD patients has long been controversial.
At the HMV centre Groningen, the majority of patients treated with NIV
therefore still concerns patients with neuromuscular diseases.
Initial trials investigating chronic NIV in COPD showed no relevant benefits,
neither in terms of improvement in gas exchange nor in improvements in
patient-centred outcomes as HRQoL. However, most of these trials used low
inspiratory pressures so that improvement of alveolar hypoventilation was not
or only partially achieved. Consequently, little improvement in clinical
outcomes could be expected.
More than 10 years ago, the concept of high-intensity NIV in COPD was
introduced. By applying higher inspiratory pressures and breathing frequencies
aimed at a more controlled form of ventilation and improvement in gas exchange,
clinically relevant improvements in HRQoL and lung function were observed,
without undue loss of patient comfort. Recently, a German group conclusively
showed that high-intensity NIV improves survival in severe COPD patients with
CHRF. These positive results with high-intensity NIV have changed our view
towards the use of chronic NIV in stable COPD. Nowadays, we believe that the
evidence for long-term nocturnal NIV is convincing and justifies the
application of this therapy in patients with severe stable COPD patients with
CHRF. Nevertheless, for a broader implementation of this treatment in a
potentially large group of severe COPD patients, important issues have to be
solved.

First, we need to reconsider the current inpatient NIV initiation process,
which despite tight titration based on arterial blood gases, does not always
lead to good patient compliance, is inconvenient for patients and is expensive.
While it might be thought that high-intensity NIV necessitates inpatient
titration to gain adequate reversal of hypoventilation, different in hospital
set ups of NIV initiation (on a general ward, medium care unit or on an
intensive care unit), with different ways of titration (guided by
transcutaneous carbon dioxide (PtCO2) or arterial blood gases (PaCO2)), have
not resulted in different outcomes or a different compliance at the long-term.
Also, these inpatient options are expensive as initiation of NIV in COPD
routinely requires 5-14 days. Recently, our group of the HMV centre Groningen
has shown that, in patients with neuromuscular and restrictive thoracic
diseases, initiation of NIV can safely be performed at home. Initiation of NIV
at home was preferred by the patients, was equally effective and saved costs
compared to inpatient initiation. Importantly, COPD patients have been excluded
in this randomised controlled trial (RCT), as at the start of that study
chronic NIV in COPD was not considered a regular standard treatment option in
the Netherlands. Furthermore, initiation of NIV in COPD patients at that time
was thought to be probably too difficult to be performed at home, because
high-intensity NIV is needed in this patient group to improve outcomes.
However, challenges with the initiation of high-intensity NIV require
attention, but do not necessarily have to be solved in-hospital. On the one
hand, patients with COPD need higher inspiratory pressures and higher backup
breathing frequencies as it is more difficult to correct alveolar
hypoventilation in lung parenchyma diseases compared to diseases in which the
lungs are not primarily affected, such as in neuromuscular disease. On the
other hand, we believe that careful high-intensity NIV initiation and titration
should not only focus on maximal improvement in PaCO2 but also on patient
comfort. The consequence of high-intensity might be that COPD patients need
even more time and attention from caregivers to get used to the high pressures
and high backup frequencies before our target can be reached, i.e. improvement
in gas exchange and respiratory muscle unloading, before the conditions also
for a good long-term compliance can be satisfied.
Finding the individual high-intensity setting leading to sufficient improvement
in objective physiological parameters is challenging in this group of patients.
This process therefore probably requires more frequent and more intensive
monitoring. At home, we will optimise monitoring of the patients with the use
of frequent non-invasive monitoring of gas exchange with transcutaneous
measurements (SenTec DM®, Software V-STATS 4.0; SenTec AG; Therwil,
Switzerland). Secondly, analysis of data read from the ventilator software
(Respironics A30 or A40®, Philips, the Netherlands) will be used to provide
information about compliance and the actual provided ventilation. Finally, we
will aid measurements of respiratory muscle activity by means of surface
electromyography (EMG) as a relatively new tool which can aid in optimising NIV
initiation.17-18 Surface EMG is a new tool that might help to optimise NIV
initiation. It has been shown that especially high-intensity NIV is able to
unload the respiratory muscles (Duiverman, work in progress). This might
importantly add to the achievement of clinical relevant benefits. Until now, no
studies have used non-invasive measurements of respiratory muscle unloading to
optimise initiation of NIV. In the last decade, I have developed and validated
a surface EMG technique for use in COPD patients, measuring respiratory muscle
activity as a surrogate of respiratory neural drive and thus muscle loading. As
this method is non-invasive, it can easily be applied at home. Furthermore,
surface EMG can be used to asses patient-ventilator asynchrony (PVA).
Especially with higher inspiratory pressures and/or high breathing frequencies
PVA may arise. PVA is important as it leads to increased work of breathing,
decreased patient comfort and less effective ventilation. During the
traditional in-hospital NIV initiation, one might suggest that an indication of
respiratory muscle (un)loading and patient-ventilator synchrony is received
through observation of the patient. However, observation by the respiratory
nurses is mostly of limited time and detects only events leading to a huge
excess of respiratory muscle loading, such as during severe PVA. During home
initiation, direct observation is far less easy and less frequent. In
concordance with a recent study showing that parasternal EMG can be used to
assess PVA in a mixed group of patients initiated on home NIV,20 we have shown
in a recent pilot project that also our surface EMG is feasible to measure
respiratory muscle unloading and detect PVA, of note, during different
settings, also high-intensity NIV (submitted work). As the use of surface EMG
for optimising NIV initiation is relatively new, we will extend the monitoring
of patients in both groups including surface EMG as a surrogate marker of
respiratory muscle unloading and to detect PVA during NIV.
For the second issue, the necessity for acclimatisation time and caregiver
attention, very elegant solutions are available to provide this at home too. A
longer initiation period can better be met at home, in a trusted environment
for the patient, saving the disadvantages and costs of a prolonged hospital
stay. With modern technologies the necessary caregiver attention can also be
provided at home. Monitoring data can be sent to caregivers on daily basis by
telemonitoring. This proven technology enables caregivers to make on daily
basis, on distance, decisions regarding the NIV initiation process, which will
be discussed with the patient by frequent telephone calls. This so called
telemedicine has already been shown to be a valuable and promising tool to
monitor and to adjust treatment of patients already established on chronic NIV
at home. In our home NIV initiation pilot project in neuromuscular patients,
we were the first to show in a RCT that this technology was very feasible to
use for NIV initiation at home.

The second important issue to be solved regards better patient selection. By
collecting the baseline and follow-up data of the COPD patients initiated on
NIV, we aim to find predictors of a favourable response to NIV. We know, from
clinical practice and from studies, that not all patients respond favourably.
Until now, data have shown that patients with CHRF benefit Furthermore,
benefits at least in terms of improvement in gas exchange, seem to be more
prominent in patients with severe stable hypercapnia. In contrast, our group
has shown that patients that remain hypercapnic after an exacerbation do not
uniformly benefit.23 An individual COPD phenotype benefiting most from this
demanding therapy has not been identified.

Primary Objective:
The aim of the present study is to investigate whether home initiation of
chronic NIV in stable COPD patients with CHRF is non-inferior to inpatient
initiation

Secondary Objective(s):
The secondary objective of the study is to collect patient demographics (age,
weight, height, social status, HRQoL, anxiety and depression scores, data on
comorbidities and medication use), respiratory function (lung function as well
as measures of respiratory muscle activity, arterial blood gases), and
inflammatory blood markers, in order to analyse how differences in baseline
parameters are related to changes in HRQoL after 6 months.

A 1:1 randomised controlled trial of non-inferiority design with minimisation
for rehabilitation status will be employed in order to test the hypothesis that
home initiation of chronic NIV is not inferior to inpatient initiation in COPD
patients with CHRF. Outcomes will be assessed after 3 and 6 months.

Additionally, from this cohort of patients, data will be collected in a
prospective manner in order to predict the response to NIV in terms of
improvement in HRQoL after 6 months of treatment

Home initiation of long-term non-invasive ventilation in COPD patients with
CHRF

Home NIV is regarded extremely safe in our patient group as these patients are
not 24-hour ventilator dependent, and with adequate hand function can always
switch off the machine and remove the mask once technical issues occur. For a
safe home initiation, as investigated in this study, we consider patient
eligible once they fulfil the same criteria as used currently for home
application of NIV, namely that patients have adequate understanding of the
machine and are capable of removing the mask. As so, we believe also initiation
of NIV at home is extremely safe.
On the other hand, we believe the benefits of home initiation of NIV can be
huge. NIV initiation which is currently performed during an hospital stay of
5-14 days which is very demanding for these end-stage COPD patients with severe
disabilities. Furthermore, for the home initiation group more noninvasive
monitoring possibilities will be used instead of invasive procedures, such as
repeated sampling of arterial blood gases.